DESCRIPTION (Adapted from the application): In both mice and humans the neuroendocrine melanocortin system has been linked to weight regulation and obesity. Of the multiple receptor subtypes involved, the melanocortin-4 receptor subtype (MC4R), which is located entirely in the central nervous system, appears to play an important role in body weight homeostasis. This is suggested most strongly by knockout and mutational studies in animals. Endogenous agonists for this receptor include proopiomelanocortin-derived peptides, whereas the agouti-related protein is a natural antagonist. However, based on the use of available agonists and antagonists, function of the MC4R is difficult to distinguish from that of other melanocortin receptor subtypes, especially MC3R, for which a function has not been defined. This lack of specificity in reagents makes it difficult to assess structure-function relationships of MC4R, and to differentiate its functions from those of MC3R. Thus, the overall goal of this proposal is to develop new peptide and non-peptide MC4R probes that can be used to define the function of the MC4R, both in vitro and in vivo. The specific aims are to 1) identify selective MC4R agonists and antagonists using peptide libraries and a combinatorial chemistry approach, 2) identify structural features of a constitutively active MC4R that will allow differentiation between agonist and antagonist behavior of ligands, and 3) test available parenteral and potential orally active compounds selective for MC4R in vivo.